Abnormal lymphangiogenesis leading to lymphedema is a common disorder afflicting tens of millions of individuals throughout the world. Yet, despite its frequency, its etiology is poorly understood and no effective therapies are available. In the present study we are focusing on the role of syndecan-2 and syndecan-4 in formation of lymphatic vasculature during development and in adult life. In preliminary studies we have demonstrated that both syndecans play a role in polarization of the lymphatic endothelium and formation of lymphatic valves. The absence of either syndecan results in formation of giant lymphatics with multiple excessive valves. These results suggest that these two syndecans are central to lymphatic development and lymphatic valve morphogenesis. We propose, therefore, to 1) define molecular mechanisms of syndecan- 2 signaling; 2) define lymphatic vasculature and lymphatic valve morphogenesis defects in syndecan-2 and 4 knockout mice and 3) investigate how syndecans 2 and 4 sense shear stress and use that ability to regulate valve formation. Taken together these studies for the first time will paint a comprehensive picture of molecular signaling events and linked physical forces that underlie formation of the lymphatic system.